Variant: NM_005629.4(SLC6A8):c.1313A>T (p.Tyr438Phe)

CA415086789

946475 (ClinVar)

Gene: SLC6A8

Condition: creatine transporter deficiency

Inheritance Mode: X-linked inheritance

UUID: b09d5230-6b1e-434b-b26e-9a80b572bad6

Approved on: 2025-05-20

Published on: 2025-05-20

HGVS expressions

NM_005629.4:c.1313A>T
NM_005629.4(SLC6A8):c.1313A>T (p.Tyr438Phe)
NC_000023.11:g.153694188A>T
CM000685.2:g.153694188A>T
NC_000023.10:g.152959643A>T
CM000685.1:g.152959643A>T
NC_000023.9:g.152612837A>T
NG_012016.1:g.10892A>T
NG_012016.2:g.10892A>T
ENST00000253122.10:c.1313A>T
ENST00000253122.9:c.1313A>T
ENST00000413787.1:c.258-16A>T
ENST00000430077.6:c.968A>T
ENST00000442457.1:c.367A>T
ENST00000485324.1:n.1458A>T
NM_001142805.1:c.1283A>T
NM_001142806.1:c.968A>T
NM_005629.3:c.1313A>T
NM_001142805.2:c.1283A>T

Uncertain Significance

• Not Met criteria codes: PP3 PM2 BS1 BS2 BP4

Expert Panel

Cerebral Creatine Deficiency Syndromes VCEP

Criteria Specification Information

Criteria Specification: ClinGen Cerebral Creatine Deficiency Syndromes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SLC6A8 Version 1.1.0

Evidence submitted by expert panel

Cerebral Creatine Deficiency Syndromes VCEP

The NM_005629.4:c.1313A>T variant in SLC6A8 is a missense variant predicted to cause the substitution of a tyrosine for a phenylalanine at amino acid position 438 (p.Tyr438Phe). To our knowledge, this variant has not been reported in the literature and no functional studies are available. In gnomAD v4.1.0. the highest population minor allele frequency (MAF) is 0.00008812 (5/56743 aleles; 1 hemizygote) in the African/African American population. This is greater than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.00002) but less than the ClinGen CCDS VCEP’s threshold for BS1 (>0.0002), such that neither of these criteria are met. There is one hemizygote in gnomAD v4.1.0. in the African/African American population. This is insufficient for the application of BS2 (2 or more hemizygotes required; BS2 not met).The computational predictor REVEL gives a score of 0.272, which is less than the ClinGen CCDS VCEP’s threshold for PP3 (>0.75) but greater than the ClinGen CCDS VCEP’s threshold for BP4 (<0.2), such that neither of these criteria are met. There is a ClinVar entry for this variant (Variation ID: 946475). In summary, this variant meets criteria to be classified as a variant of uncertain significance for creatine transporter deficiency. SLC6A8-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): no criteria met. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on May 20, 2025)

Not Met criteria codes

• PP3: The computational predictor REVEL gives a score of 0.219, which is less than the ClinGen CCDS VCEP’s threshold for PP3 (>0.75) but greater than the ClinGen CCDS VCEP’s threshold for BP4 (<0.2), such that neither of these criteria are met. SpliceAI suggests that the variant has no impact in splicing (Acceptor Gain 0.14, score must be >0.2 to suggest impact on splicing)
• PM2: In gnomAD v4.1.0. the highest population minor allele frequency (MAF) is 0.00008812 (5/56743; 1 hemizygote) in the African/African American population. This is greater than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.00002) but less than the ClinGen CCDS VCEP’s threshold for BS1 (>0.0002), such that neither of these criteria are met.
• BS1: In gnomAD v4.1.0. the highest population minor allele frequency (MAF) is 0.00008812 (5/56743; 1 hemizygote) in the African/African American population. This is greater than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.00002) but less than the ClinGen CCDS VCEP’s threshold for BS1 (>0.0002), such that neither of these criteria are met.
• BS2: There is one hemizygote in gnomAD v4.1.0. in the African/African American population. This is insufficient for the application of BS2 (2 or more hemizygotes required).
• BP4: The computational predictor REVEL gives a score of 0.219, which is less than the ClinGen CCDS VCEP’s threshold for PP3 (>0.75) but greater than the ClinGen CCDS VCEP’s threshold for BP4 (<0.2), such that neither of these criteria are met.